Molecular mechanisms of tamoxifen-associated endometrial cancer (Review)

Oncol Lett. 2015 Apr;9(4):1495-1501. doi: 10.3892/ol.2015.2962. Epub 2015 Feb 12.


Tamoxifen has been prescribed to millions of females for breast cancer prevention or treatment. However, tamoxifen is known to significantly enhance the risk of developing endometrial lesions, including hyperplasia, polyps, carcinomas, and sarcoma. Notably, tamoxifen-associated endometrial cancer often has a poor clinical outcome. Understanding the molecular mechanism of tamoxifen-induced endometrial cancer is essential for developing strategies that minimize tamoxifen's effects on the endometrium without jeopardizing its breast cancer treatment effects. However, this understanding remains limited. Tamoxifen appears to mediate its effect on endometrial cells through estrogenic and non-genomic pathways, rather than introducing a genomic alteration as a carcinogen. Although tamoxifen functions as an agonist and promotes cell proliferation in endometrial cancer, it also displays antagonist activity towards some estrogen targets. Alterations in estrogen receptor-α and its isoforms, as well as the membrane associated estrogen receptor G protein-coupled receptor 30, have been observed with tamoxifen-exposed endometrial cells, and likely mediate the effects of tamoxifen on endometrial cancer cell proliferation and invasion. In addition, gene profile studies of short-term exposure to tamoxifen indicate that the majority of tamoxifen targets are tamoxifen-specific. However, the tamoxifen regulated gene targets that are involved in mediating the effects of long-term exposure to tamoxifen are not yet fully understood. Recent progress has indicated a potential role of unfolded protein response and mammalian target of rapamycin signaling in tamoxifen-associated endometrial cancer. In the future, studies focusing on long-term effects of tamoxifen exposure are required to understand the molecular mechanisms of tamoxifen-associated endometrial cancer.

Keywords: G protein-coupled receptor 30; Tamoxifen; autophagy; endometrial cancer; estrogen receptor; unfolded protein response.